We propose to maintain and to continuously improve the NIDA Neuroproteomics Center at the Yale University School of Medicine. Faculty members from Yale and other institutions (Univ. Chicago, Univ. Connecticut, Rockefeller Univ., Stanford Univ., Univ. Texas) with established records of research into the molecular actions of psychostimulants and psychotropic drugs, as well as of other basic aspects of neurobiology, will continue to work together with members of the W.M. Keck Foundation Laboratory to create the NIDA Neuroproteomics Center. The main goal of the Center is to apply high-throughput, state-of-the-art proteomic methods to analyze adaptive changes in neuronal protein expression and regulation that occur in response to drugs of abuse. In addition, the Center will provide training in proteomics technologies for members of the Center, and will apply new proteomics technologies to answer biological questions related to the actions of drugs of abuse. Under the direction of Dr. Kenneth Williams (Center Director) and Dr. Angus Nairn (Co-Investigator, Psychiatry) in the Administration Core, the Center will include a Protein Profiling and Identification Core, a Protein Post-translational Identification and Profiling Core, and a Targeted Proteomics Core. Lipid and Biophysics analyses will be included in the Protein Profiling Core. Finally, a Protein Database, Biostatistics, Bioinformatics and a High Performance Computing Core will provide essential support that will positively leverage the value of each of the proteomic technology cores. The behavioral adaptations that accompany drug addiction are believed to result from both short and long-term adaptive changes in brain reward centers. Thus, exposure to drugs of abuse regulates intracellular signaling processes and in turn results in alteration of gene expression, protein translation and post-translational modifications of proteins. Repeated exposure to drugs of abuse leads to long-term, stable alterations in these signaling systems that are critical for the changes in brain chemistry and structure of the addicted brain. The Center, through its multidisciplinary and collaborative organization, brings together Yale faculty and their collaborators to gain a deeper insight into the mechanisms of neuronal signaling processes and into how drugs of abuse alter these signaling mechanisms. Specific goals of the research supported by the Center will include analysis of the actions of the psychostimulants, cocaine and amphetamine, nicotine and opiates. Newly developed methods will be applied to the study of protein phosphorylation and other post-translational modifications of neuronal proteins, as well as to the targeted analysis of neuronal proteins implicated in the actions of drugs of abuse. PUBLIC HEALTH RELEVANCE: Drugs of abuse usurp and modify communication between neurons, resulting in stable changes in the expression and activities of proteins (the "neuroproteome") required for normal neuronal function. Improving our fundamental understanding of how drugs of abuse alter the neuroproteome will provide deeper insight into the process of drug addiction and thus help in the design of new therapeutic strategies.